The Role Of 14-3-3 Proteins In Regulating The Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
The immune response is the body's defense system. It's malfunction leads to many diseases such as immune deficiency, asthma and cancer. Thus, it is important to find genes controlling immunity. Significantly, mammals have amazing similarities with flies, in terms of genes controlling immunity. We have found a new regulator of fly immunity and will define how this gene functions in the immune system. This project will identify potential points of intervention for treating immune system disorders.
Structural Diversity And Evolution Of Variant-specific Surface Proteins In The Protozoan Parasite, Giardia
Funder
National Health and Medical Research Council
Funding Amount
$436,417.00
Summary
Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect ....Giardia are well-known as a cause of travellers' diarrhoea, but our knowledge about these parasites remains rudimentary. Infections are common in Australia, especially in day-care centres and outback Aboriginal communities. The 1998 Sydney water crisis highlighted the necessity of monitoring reservoirs and reticulated water for contamination by faecal cysts of both human and animal origin. The aim of this project is to learn more about the 'coat' proteins which cover the organisms. These protect the parasites against digestion, enabling them to reside indefinitely within the intestine. However, the proteins are also the principal target of host immunity. Analysis of Giardia populations has shown that as many as 150-200 different coat proteins can be made. Although individual cells have coats comprised of only a single protein type, these can 'switch' spontaneously to production of another type - a phenomenon known as 'antigenic variation'. This process occurs slowly but continuously, giving rise to 'variants' which survive successive host responses (directed against each predominant coat type) and occupy the vacancies left by the destruction of their immediate forebears. It is important to gain information about the structural diversity of these variant-specific proteins (VSP), as any 'Giardia' vaccine is likely to require inclusion of each major type. It is also important to elucidate how the 'switching' process occurs, as this may provide clues as to how it might be interrupted. The project addresses both aspects.Read moreRead less
Immunochemical And Functional Studies On A Novel Protein Of Plasmodium Falciparum Containing EGF-like Domains
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focuses on developing a better understanding of how the malaria parasite fu ....Malaria infection of humans is one of the most important and deadly infectious diseases in the world, killing more than two million people each year. Traditionally, drugs and insecticides have been used to treat the disease and control its spread. Unfortunately, both of these have become much less effective and there now exist untreatable cases of malaria. Alternative control measures are urgently needed and this project focuses on developing a better understanding of how the malaria parasite functions. If important processes such as red blood cell invasion can be understood in detail then it becomes possible to identify proteins essential for survival of the parasite. These could then be used as a vaccine against the disease. Current work suggests that the vaccine will be need more than one parasite protein and it becomes essential to identify the best combination of components. The parasite protein called MSP1 is thought to be a very promising candidate, but it is insufficiently active on its own. We have recently discovered a new protein in the human malaria parasite Plasmodium falciparum, that is similar to MSP1. We would like to know more about this protein and determine if it may be a useful addition to MSP1 for a vaccine. This project intends to further characterize the properties of this new protein including its role in red blood cell invasion and to examine whether immunization with the rodent malaria form of the protein is able to protect mice against malaria infection. The results of this project will be highly significant in the field of malaria vaccine development and will indicate whether this new protein will be a useful component of the eventual malaria vaccine.Read moreRead less
Structural And Functional Properties Of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$188,623.00
Summary
Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protei ....Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a member of the Ig-superfamily that is implicated in a variety of biological responses such as leukocyte transmigration, angiogenesis, cellular signaling, cell adhesion and migration. Recent studies from this laboratory has demonstrated that PECAM-1 contains intracytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIM) that upon phosphorylation can mediate an inhibitory function through recruitment and activation of protein tyrosine phosphatases, SHP-1 and SHP-2. We would therefore consider PECAM-1 as a new member of an emerging Ig-ITIM superfamily. Members of the Ig-ITIM gene family have both inhibitory-non-inhibitory receptors which upon ligation of specific receptors can globally stimulate or inhibit cellular activation in the context of B cells, Tcells, mast cells , endothelial cells or platelets. Balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease, to provoke immunological memory from vaccination and to dampen the extent and duration of platelet activation. Our investigations are focussing on the isolation and functional characterisation of PECAM-1 family members to define their role in regulating cell signaling pathways in vascular and haematopoietic cells. We predict that PECAM-1 has numerous undefined family members that exist as multiple isoforms as a product of separate genes, alternative splicing of discrete exons and single point mutations giving rise to conservative and non-conversative amino acid changes. The longer term potential of this study is to provide knowledge for understanding the structural and functional roles of PECAM-1 isoforms in physiological cells in health and disease. This knowledge could then be applied to provide targets for novel therapeutic interventions in the clinical management of autoimmune disease, humoral and inflammatory responses.Read moreRead less